Chemical compounds



Patented Dec. 24, 1946 E. 'Harris,fiN utley;,. N. J assignors to E. B. Squibb, & Sons, New ,York, N; Y.,-'a corporation of New York No, Drawing. Original application September 9, 1937, Serial mid-163,034. Divided and this a -v plication- June 28, 1944, Serial'No'. 542,619

Claimsg/ 01. 260- 473.)

This application is a division of our application Serial No. 163,034, filed September 9, 1937.

This invention relates to, and has for its object the provision of, certain amino-alcohol esters". of

oxy-benzoic acids, and 'aci'd addition salts thereof. These estershave thegeneral formula where R is an alkyl residue with 3m 4 carbon atoms, R is analkylene residue, and R and R are two alkyl residues. 1

The compounds of this invention are valuable therapeutic agents, being,particularlyeifective for inducing local anesthesia; r

In the practice of this invention; an aracyl halideof the general formula), .1, v

is reacted with an alcohol oithe formulato produce the desired ester, R, R R and R having the above-noted signification.

The amino-esters of this invention are generally recovered in the form of their additionsalts with hydrochloric acid. However, other acids forming addition salts with amines may be used in place of hydrochloric; such acids are boric, nitric, lactic, tartaric, citric, phosphoric, sulfuric, picric and 'picrolonic. The additionsalts may be converted intolthe .free bases in the usual manner.

Thefollowing examples are I illustrative of the invention:

EXAMPLE 1 ,B-Dz'ethyZamino-ethyi ester of p-n-butoacybenzoic acid A solution of 10.5 g. of p-n-butoxy-benzoyl chloride in 25 cc. of dry benzene is refluxed for two hours with a solution comprising 6.14 g. of fi-diethylamino-ethanolin cc. of dry benzene; the solution is allowed to cool and the hydrochloride of the desired ester separates as a heavy crystalline deposit; after filtering and washing theprecipitatewithbenzene and dry ether a compound having a melting point of 146 C. (corrected) is obtained;

EXAMPLE 2 e-Dimcthylamino-ethyl ester of p-n-butoacy benzoicacid 4.5 g. of fl-dimethylamino-ethanol dissolved in 10 cc; of dry benzene is treated with a solution comprising 10.5 g. of p-n-butoxyrbenzoyl chloride in '20 cc.of dry benzene; filtering oil the precipitate and washing it with benzene and petroleum ether yields the hydrochloride of the desired ester,

having a melting point of 132-133? C.

EXAMBlZE' 3 Gamma-diethylamino-(,c-hydroxyl-propyl ester of p-n-butoxy-benzoic acid A solution ofi5 g. of l-diethylaminc-2,3-pro-' panediol, '6.2 g. 'of p-n-butoXy-benzoyl chloride and 10 g. of potassium carbonate, in'50 cc. of benzene, is refluxed for minutes.

filtrate, the resultant solution being evaporated to dryness.; Recrystallizing the residue from alcohol and dry ether yields the desired product,

which a mixtureof twoisomers, and has no sharp melting point' (79l96 (3.). 7

EXAMPLE 4 a,a-di-(Ndimethylaminomethyl) en-propyl ester of p-n-butory-b-enzoic acid 1.5v 2:. r 1,B-di-dimethylamino-Z-ethyl propan0l-2' and 1.6 g; of p-n butoxy-benzoic acid ,are 7 each dissolved in 5 cc. of chloroform, and the mixtureof the solutionsis heated on a steam bath for "5 minutes. Adding dry ether, filtering the precipitate formed; washing and drying the filter,

cake, yields the hydrochloride of the desired product having a melting point of 111 C.

EXAMPLE 5 ,e-DiethyZamino-ethyl ester of p-n-propoaiybenzoic acid ter mixing and refiuxin solutions comprising 9.5 g. of p-n-propoxy-benzoyl chloride and 11.2 g. of diethyl-amino-ethanol, each dissolved in 25 cc. of benzene, for 30 minutes, the reaction mixture is cooled, and cc. of dilute sodium hydroxide solution is added; then after vigorously shaking On cooling overnight, the precipitate formed is filtered oil and alcoholic hydrochloric acid is added to the 3 the mixture, the benzene layer, containing the desired ester, separates and is decanted off. Then washing the benzene solution with water, distilling off the benzene, and vacuum-distilling the residue, yields the desired ester, having a boiling point of 160-165 C./4 mm.

The hydrochloride is obtained (by dissolving this product in alcoholic hydrochloric acid and precipitating with ether) in the form of a white crystalline solid, melting at 135l3'7 C.

EXAMPLE 6 p-Diethylamino-ethyl ester of p-isopropozcybenzoic acid EXAMPLE '7 p-Diethylamz'no-ethyl ester of p-aZZyloxy-beneoic acid This compound is prepared in the same manner as that of Example 6, except that 8 g. of p-allyl oxy-benzoyl chloride (instead of the p-n-propoxy derivative) and 9.5 g. of diethyl-amino-ethanol are used. The boiling point of the ester is 165- 175 C./4 mm. The hydrochloride melts at 130 C.

EXAMPLE 8 c-Diethylamino-ethyl ester of p-(c-bromallylozcy) -beneoic acid A solution comprising 17 g. methyl p-hydroxybenzoate and 25 g. 2,3-dibromopropene and a suspension of 20 g. potassium carbonate in 50 cc. of acetone is refluxed, with stirring, for

ill

hours; filtering the mixture, evaporating the acetone from the filtrate, hydrolyzing the residue by heating with aqueous sodium hydroxide, precipitating the free acid with hydrogen chloride, and after filtering, washing and drying the precipitate, recrystallizing it from benzene, yields the desired intermediate, p-(fi-bromallyloxy)-benzoic acid, melting at 200 C. (with decomposition). Warming 9.5 g. of this benzoic acid derivative with 7.7 g. of phosphorus pentachloride and fractionating the mixture in vacuo, yields the desired acid chloride intermediate, boiling at 160-170 C./5 mm.

Refluxing a mixture comprising 6 g. of this p-(fi-bromalloxy)-benzoyl chloride and 5.1 g. of diethylamino-ethanol, each dissolved in 25 cc. of dry benzene, for half an hour, filtering off the precipitate and treating the filtrate with alcoholic hydrochloric acid, yields, after evaporating the benzene and hydrogen chloride and recrystallizing the residue from alcohol and ether, the desired compound melting at 81.583.5 C.

EXAMPLE 9 fl,B'-di(dimethylamino) -isopropyl ester of 17-11- propomy-benzoz'c acid (hydrochloride) 2 g. J8,;9-di-(dimethylamino)-isopropanol and 3.2 g. p-n-propoxy benzoyl chloride are each dissolved in 5 cc. chloroform and the solutions mixed. A precipitate forms, which is dissolved by adding dry acetone, and the reaction completed by warmingfor a short time on the water bath. The solvents are then distilled off, and the residue recrystallized from a mixture of alcohol and ether. The product, which melts at 208 C. with decomposition, is a mixture of the monoand di-hydrochlorides.

The following are among the many. other compounds embraced by the present invention, and may be prepared according to the directions given above:

Ewample 10.-d-Benzyl-d-diethylaminoinethyb propyl ester of p-n-butoxy-benzoic acid.

Example 11 .a-Methyl-d-diethylaminomethyln-butyl ester of p-n-propoxy-benzoic acid.

The invention may be variously otherwise embodied, within the scope of the appended claims.

We claim:

1. A water soluble salt of a dialkylamino alkanol ester of a p-alkoxy benzoic acid of the following type:

p-RO CllHiG 0 0 Rm H s It Ac where R is an aliphatic hydrocarbon residue with 3 to 4 carbon atoms, R is an ethylene residue, R and R are two ethyl residues, and Ac is an acid radical forming a water soluble salt with the ester of the amino alcohol.

2. A water soluble salt of a dialkylamino alkanol ester of a p-alkoxy benzoic acid of the following type:

WALTER G. CHRISTIANSEN. SIDNEY E. HARRIS. 

